Adenosine in fibrosis

Chan, Edwin S. L.; Cronstein, Bruce N.

doi:10.1007/s10165-009-0251-4

Cited by 29 publications

(31 citation statements)

References 81 publications

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“…The beneficial effects of adenosine in other models of lung inflammation and fibrosis make it highly likely that therapeutic inhibition of CD73 may blunt protective effects of CD73-dependent adenosine signaling that limit radiation-induced tissue damage and the resulting inflammation particularly during acute disease stages. For example, ADORA2A signaling via CD73-generated adenosine may suppress inflammatory functions of the innate and adaptive immune systems, modulate angiogenesis and matrix-induced pro-inflammatory and pro-fibrotic signaling, and induce Tregs which are known to contribute to adenosine-mediated resolution of acute lung injury (17, 46). Intriguingly, we observed pulmonary accumulation of CD73 + CD4 + FoxP3 + Tregs during the pneumonitic and fibrotic phases upon WTI.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis

et al. 2016

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Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5'-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks post-irradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately three-fold. Histological evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P<0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase (PEG-ADA) or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacological strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies.

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Section: Discussionmentioning

confidence: 99%

Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis

et al. 2016

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“…; Kumar and Sharma ). Moreover, adenosine protects against ischemia–reperfusion injury (Eltzschig ), modulates fibrosis (Chan and Cronstein ), and facilitates wound healing (Feoktistov et al. ; Valls et al.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cell proliferation by the guanosine-adenosine mechanism: role of adenosine receptors

Jackson

Gillespie

2013

Physiol Rep

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A recent study (American Journal of Physiology-Cell Physiology 304: C406–C421, 2013) suggests that extracellular guanosine increases extracellular adenosine by modifying the disposition of extracellular adenosine (“guanosine-adenosine mechanism”) and that the guanosine-adenosine mechanism is not mediated by classical adenosine transport systems (SLC28 and SLC29 families) nor by classical adenosine-metabolizing enzymes. The present investigation had two aims: 1) to test the hypothesis that the “guanosine-adenosine mechanism” affects cell proliferation; and 2) to determine whether the transporters SLC19A1, SLC19A2, SLC19A3 or SLC22A2 (known to carrier guanosine analogues) might be responsible for the guanosine-adenosine mechanism. In the absence of added adenosine, guanosine had little effect on the proliferation of coronary artery vascular smooth muscle cells (vascular conduit cells) or preglomerular vascular smooth muscle cells (vascular resistance cells). However, in the presence of added adenosine (3 or 10 μmol/L), guanosine (10 to 100 μmol/L) decreased proliferation of both cell types, thus resulting in a highly significant (p<0.000001) interaction between guanosine and adenosine on cell proliferation. The guanosine-adenosine interaction on cell proliferation was abolished by 1,3-dipropyl-8-(p-sulfophenyl)xanthine (adenosine receptor antagonist). Guanosine (30 μmol/L) increased extracellular levels of adenosine when adenosine (3 μmol/L) was added to the medium. This effect was not reproduced by high concentrations of methotrexate (100 μmol/L), thiamine (1000 μmol/L), chloroquine (1000 μmol/L) or acyclovir (10,000 μmol/L), archetypal substrates for SLC19A1, SLC19A2, SLC19A3, and SLC22A2, respectively; and guanosine still increased adenosine levels in the presence of these compounds. Conclusion: The guanosine-adenosine mechanism affects cell proliferation and is not mediated by SLC19A1, SLC19A2, SLC19A3 or SLC22A2.

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“…Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair (2). Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses (3, 4), prolonged elevations in adenosine can enhance destructive tissue remodeling processes associated with chronic disease states (5, 6). Consistent with this paradigm, adenosine serves as an anti-inflammatory molecule in models of acute lung injury (7-10), whereas elevations in adenosine contribute to disease progression in models of chronic lung disease (11, 12).…”

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confidence: 99%

Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury

Zhou¹,

Schneider²,

Morschl³

et al. 2011

The Journal of Immunology

104

118

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Adenosine is an extracellular signaling molecule that is generated in response to cell injury where it orchestrates tissue protection and repair. Whereas adenosine is best known for promoting anti-inflammatory activities during acute injury responses, prolonged elevations can enhance destructive tissue remodeling processes associated with chronic disease states. The generation of adenosine and the subsequent activation of the adenosine 2B receptor (A2BR) is an important processes in the regulation of both acute and chronic lung disease. The goal of this study was to examine the contribution of the A2BR in models of bleomycin-induced lung injury that exhibit varying degrees of acute and chronic injury. Intratracheal bleomycin exposure results in substantial acute lung injury followed by progressive fibrosis. In this model, genetic removal of the A2BR resulted in enhanced loss of barrier function and increased pulmonary inflammation, with few differences in indexes of pulmonary fibrosis. These results support an anti-inflammatory role for this receptor in this model of acute lung injury. In contrast, systemic exposure of mice to bleomycin resulted in modest acute lung injury together with progressive pulmonary fibrosis. In this model, the effects of A2BR removal on acute lung injury were negligible; however, there were substantial reductions in pulmonary fibrosis, supporting a profibrotic role for this receptor. A2BR-dependent regulation of IL-6 production was identified as a potential mechanism involved in the diminished pulmonary fibrosis seen in A2BR knockout mice exposed to i.p. bleomycin. These studies highlight the distinct roles of A2BR signaling during acute and chronic stages of lung injury.

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Adenosine in fibrosis

Cited by 29 publications

References 81 publications

Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis

Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis

Regulation of cell proliferation by the guanosine-adenosine mechanism: role of adenosine receptors

Distinct Roles for the A2B Adenosine Receptor in Acute and Chronic Stages of Bleomycin-Induced Lung Injury

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